The invention relates to a process for the preparation of a compound of the formula 
and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in each case in free form or in salt form, wherein
Q is CH or N,
Y is NO2 or CN,
Z is CHR3, O, NR3 or S,
R1 and R2 are either each independently of the other hydrogen or unsubstituted or R4-substituted C1-C8alkyl, or together form an alkylene bridge having two or three carbon atoms, and said alkylene bridge may additionally contain a hetero atom selected from the group consisting of NR5, O and S,
R3 is H or unsubstituted or R4-substituted C1-C12alkyl,
R4 is unsubstituted or substituted aryl or heteroaryl, and
R5 is H or C1-C12alkyl;
which comprises
a) reacting a compound of the formula 
xe2x80x83and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in each case in free form or in salt form, which is known or can be prepared by processes known per se and wherein
R is unsubstituted or substituted C1-C12alkyl, unsubstituted or substituted C2-C4alkenyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or -SR6; and
R6 is unsubstituted or substituted C1-C12alkyl, unsubstituted or substituted C2-C4alkenyl, unsubstituted or substituted C2-C4alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycyl,
X1 is a leaving group;
with a halogenating agent, in the presence of a base, to form a compound of the formula 
or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or a tautomer thereof, wherein
R is as defined for formula (II);
m is 0 or 1; and
X is halogen; or
b) converting a compound of formula (II) by means of a halogenating agent into a compound of the formula 
xe2x80x83or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or a tautomer thereof, wherein R, X and X1 are as defined above for formulae (II) and (III); optionally
c) converting a compound of formula (IV), in the absence or in the presence of a base, preferably in the presence of a base, into a compound of formula (III);
d) converting a compound of formula (III) by means of a compound of the formula 
xe2x80x83or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or a tautomer thereof, in each case in free form or in salt form, which is known or can be prepared by processes known per se and wherein R1, R2, Y, Z and Q are as defined above for the compound of formula (I), into a compound of the formula 
xe2x80x83or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or a tautomer thereof, in each case in free form or in salt form, which is known or can be prepared by processes known per se and wherein R1, R2, Y, Z and Q are as defined above for the compound of formula (I) and R is as defined above for the compound of formula (II); or
e) converting a compound of formula (IV) by reaction with a compound of formula (V) into a compound of formula (VI); and
f) converting a compound of formula (VI) by means of a chlorinating agent into a compound of formula (I);
and in each case, if desired, converting a compound of formula (I) obtainable in accordance with the process or by another method, or an E/Z-isomer or tautomer thereof, in each case in free form or in salt form, into a different compound of formula (I) or an E/Z-isomer or tautomer thereof, in each case in free form or in salt form, separating a mixture of E/Z-isomers obtainable in accordance with the process and isolating the desired isomer, and/or converting a free compound of formula (I) obtainable in accordance with the process or by another method, or an E/Z-isomer or tautomer thereof, into a salt or converting a salt, obtainable in accordance with the process or by another method, of a compound of formula (I) or of an E/Z-isomer or tautomer thereof into the free compound of formula (I) or an E/Z-isomer or tautomer thereof or into a different salt.
Methods of synthesis for the compounds of formula (I) are described in the literature. It has been found, however, that the intermediates that have to be used in those synthesis processes known in the literature cause considerable problems during production on account of their high level of toxicity and, moreover, can be removed quantitatively from the active substance only with a significant outlay. Accordingly, the known processes are not satisfactory in that respect, giving rise to the need to make available improved preparation processes for those compounds.
Some compounds of formulae (I), (II), (III), (IV), (V) and (VI) contain asymmetric carbon atoms, as a result of which the compounds may occur in optically active form. Formulae (I) to (VI) are intended to include all those possible isomeric forms as well as mixtures thereof, for example racemates or mixtures of E/Z-isomers.
The general terms used hereinbefore and hereinafter have the meanings given below, unless defined otherwise:
Unless defined otherwise, carbon-containing groups and compounds each contain from 1 up to and including 8, preferably from 1 up to and including 6, especially from 1 up to and including 4, more especially 1 or 2, carbon atoms.
Alkylxe2x80x94both as a group per se and as a structural element of other groups and compounds, such as haloalkyl, arylalkyl or hydroxyalkylxe2x80x94is, in each case giving due consideration to the number of carbon atoms contained in the group or compound in question, either straight-chained, i.e. methyl, ethyl, propyl, butyl, pentyl or hexyl, or branched, for example isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl or isohexyl.
Alkenylxe2x80x94both as a group per se and as a structural element of other groups and compounds, such as haloalkenyl or arylalkenylxe2x80x94is, in each case giving due consideration to the number of carbon atoms contained in the group or compound in question, either straight-chained, for example vinyl, 1-methylvinyl, allyl, 1-butenyl or 2-hexenyl, or branched, for example isopropenyl.
Alkynylxe2x80x94both as a group per se and as a structural element of other groups and compounds, such as haloalkynylxe2x80x94is, in each case giving due consideration to the number of carbon atoms contained in the group or compound in question, either straight-chained, for example propargyl, 2-butynyl or 5-hexynyl, or branched, for example 2-ethynylpropyl or 2-propargylisopropyl.
C3-C8 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclo hexyl.
Aryl is phenyl or naphthyl, especially phenyl.
Heterocyclyl is understood as being a five- to seven-membered monocyclic saturated or unsaturated ring that contains from one to three hetero atoms selected from the group consisting of N, O and S, especially N and S, or a bicyclic ring that may contain either in only one ringxe2x80x94such as, for example, thiazolyl, thiazolinyl, thiazolidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, quinolinyl, quinoxalinyl, indolinyl, benzothiophenyl or benzofuranylxe2x80x94or in both ringsxe2x80x94such as, for example, in pteridinyl or purinylxe2x80x94independently of one another, one or more hetero atoms selected from N, O and S. Preference is given to thiazolyl, thiazolinyl, pyridyl, pyrimidinyl and benzothiazolyl. Heteroaryl is an aromatic mono- or bicyclic ring of the type defined above.
The said heterocyclyl rings are optionally substituted with one to three substituentsxe2x80x94according to substitution possibilities on the ring systemxe2x80x94selected from the group consisting of halogen, C1-C4alkyl, halogen-C1-C4alkyl and X, wherein X, is as defined hereinbelow. Preferred are chlorine and xe2x80x94CH2Cl.
Halogenxe2x80x94both as a group per se and as a structural element of other groups and compounds, such as haloalkyl, haloalkenyl and haloalkynylxe2x80x94is fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine, more especially chlorine or bromine, very especially chlorine.
Halo-substituted carbon-containing groups and compounds, such as haloalkyl or haloalkenyl, may be partially halogenated or perhalogenated, the halogen substituents in the case of multi-halogenation being the same or different. Examples of haloalkylxe2x80x94both as a group per se and as a structural element of other groups and compounds, such as haloalkenylxe2x80x94are methyl substituted from one to three times by fluorine, chlorine and/or by bromine, such as CHF2 or CF3; ethyl substituted from one to five times by fluorine, chlorine and/or by bromine, such as CH2CF3, CF2CF3, CF2CCl3, CF2CHCl2, CF2CHF2, CF2CFCl2, CF2CHBr2, CF2CHClF, CF2CHBrF or CClFCHClF; propyl or isopropyl substituted from one to seven times by fluorine, chlorine and/or by bromine, such as CH2CHBrCH2Br, CF2CHFCF3, CH2CF2CF3 or CH(CF3)2; and butyl or an isomer thereof substituted from one to nine times by fluorine, chorine and/or by bromine, such as CF(CF3)CHFCF3 or CH2(CF2)2CF3. Haloalkenyl is, for example, CH2CHxe2x95x90CHCl, CH2CHxe2x95x90CCl2, CH2CFxe2x80x94CF2 or CH2CHxe2x95x90CHCH2Br.
A leaving group X1 is hereinbefore and hereinafter understood as being all in connection with chemical reactions atoms or groups which can act as leaving groups and which are known to the artisan. Preferred are halogen, such as fluorine, chlorine, bromine and iodine; xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94A, xe2x80x94Oxe2x80x94P(xe2x95x90O)(xe2x80x94A)2, xe2x80x94Oxe2x80x94Si(C1-C8-Alkyl)3, xe2x80x94Oxe2x80x94(C1-C8-Alkyl), xe2x80x94Oxe2x80x94Aryl, xe2x80x94Oxe2x80x94S(xe2x95x90O)2A, xe2x80x94Sxe2x80x94P(xe2x95x90O)(xe2x80x94A)2, xe2x80x94Sxe2x80x94P(xe2x95x90S)(xe2x80x94A)2, xe2x80x94Sxe2x80x94Sxe2x80x94(C1-C8-Alkyl), xe2x80x94Sxe2x80x94S-Aryl, xe2x80x94Sxe2x80x94(C1-C8-Alkyl), xe2x80x94Sxe2x80x94Aryl, xe2x80x94S(xe2x95x90O)A, or xe2x80x94S(xe2x95x90O)2A, wherein A is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkinyl, aryl or benzyl, which are unsubstituted or substituted; C1-C8-alkoxy or di-(C1-C8-alkyl)amin, wherein the alkyl groups are independent of each other; NO3, NO2, sulfate, sulfite, phosphate, phosphite, carboxylate, iminoester, N2 or carbamate. Preferred leaving groups are chlorine and bromine, especially chlorine. Other preferred leaving groups are given in the examples.
Some compounds of formulae (I), (V) and (VI) may be in the form of tautomers. Therefore, hereinbefore and hereinafter the compounds of formulae (I), (V) and (VI) are to be understood as including also the corresponding tautomers, even if the latter are not mentioned specifically in every case.
Compounds of formulae (I), (II), (III), (V) and (VI) that have at least one basic centre are able to form, for example, acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example perchloric add, sulfuric acid, nitric acid, nitrous acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as unsubstituted or substituted, for example halo-substituted, C1-C4alkane-carboxylic acids, for example acetic acid, saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric or phthalic acid, hydroxycarboxylic acids, for example ascorbic, lactic, malic, tartaric or citric acid, or benzoic acid, or with organic sulfonic acids, such as unsubstituted or substituted, for example halo-substituted, C1-C4alkane- or aryl-sulfonic acids, for example methane- or p-toluene-sulfonic acid. Moreover, compounds of formulae (I), (II), (III), (IV), (V) and (VI) having at least one acid group are able to form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, diethyl-, triethyl- or dimethyl-propyl-amine, or a mono-, di- or tri-hydroxy-lower alkylamine, for example mono-, di- or tri-ethanolamine. Furthermore, corresponding internal salts may be formed. Hereinbefore and hereinafter, the compounds of formulae (I) to (VI) are to be understood as being both the compounds of formulae (I) to (VI) in free form and the corresponding salts. The same applies to tautomers of compounds of formulae (I), (V) and (VI) and their salts. In the case of the compounds of formulae (I) to (III), (V) and (VI), preference is in each case generally given to a process for the preparation of the free form.
Within the scope of the invention, preference is given to a process for the preparation of a compound of formula (I) wherein
(1) R1 and R2 in the compounds of formulae (I), (V) and (VI) are either each independently of the other hydrogen or C1-C4alkyl, or together form a alkylene bridge containing 2 or 3 carbon atoms, that may additionally contain a hetero atom selected from the group consisting of O and S, or may contain the group NR5, and R5 is H or C1-C4 alkyl; especially, R1 and R2 are each hydrogen or together form a two- or three-membered alkylene bridge that may additionally contain O or NR5, and R5 is C1-C4alkyl;
more especially, R1 and R2 together are xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94;
(2) R in the compounds of the formulae (II), (III), (IV) and (VI) is unsubstituted or substituted C1-C12alkyl; unsubstituted or substituted aryl-C1-C4alkyl; unsubstituted or halo-substituted heterocycyl-C1-C4alkyl, aryl-C2-C4alkenyl or heterocycyl-C2-C4alkenyl; unsubstituted or halo-substituted C2-C4alkenyl, C2-C4 alkynyl, aryl -C2-C4alkynyl, heterocycyl-C2-C4alkynyl or C4-C6cycloalkyl; unsubstituted or halo-, C1-C4alkyl-, HOxe2x80x94C1-C4alkyl- or HSxe2x80x94C1-C4alkyl-substituted aryl; unsubstituted or halo- or C1-C4alkyl-substituted heterocycyl; xe2x80x94CH2COOxe2x80x94C1-C8alkyl, xe2x80x94CH2xe2x80x94COxe2x80x94C1-C8alkyl, SR6, xe2x80x94(CH2)nxe2x80x94SR6 or xe2x80x94CH2xe2x80x94COO-M, wherein M is hydrogen or a cation and n is from 1 to 8;
especially unsubstituted or halo-, OHxe2x80x94 or SH-substituted C1-C12alkyl; unsubstituted or halo-substituted aryl-C1-C4alkyl; unsubstituted or halo-substituted heteroaryl-C1-C4alkyl, aryl-C1-C4alkenyl or heteroaryl-C1-C4alkenyl; unsubstituted or halo-substituted C2-C4alkenyl, C2-C4alkynyl, aryl-C2-C4alkynyl, heteroaryl-C2-C4alkynyl or C4-C6cycloalkyl; unsubstituted or halo-, C1-C4alkyl-, HOxe2x80x94C1-C4alkyl- or HSxe2x80x94C1-C4alkyl-substituted aryl; unsubstituted or halo- or C1-C4alkyl-substituted heteroaryl; xe2x80x94CH2xe2x80x94COOxe2x80x94C1-C8alkyl, xe2x80x94CH2xe2x80x94COxe2x80x94C1-C8alkyl, SR6, xe2x80x94(CH2)nxe2x80x94SR6 or xe2x80x94CH2xe2x80x94COO-M, wherein M is hydrogen, an alkali metal cation or (alkyl)4N⊕ and n is from 1 to 8;
more especially C1-C4alkyl, hydroxy-C1-C4alkyl, C3-C4alkenyl, C3-C4alkynyl, chloro-C3-C4-alkenyl, unsubstituted or chlorine-substituted phenyl, unsubstituted or chlorine-substituted benzyl, heterocyclyl, cyclohexyl, xe2x80x94CH2COOxe2x80x94C1-C4alkyl;
very especially C1-C4alkyl, phenyl, benzyl, cyclohexyl, thiazolyl, benzothiazol-2-yl, xe2x80x94CH2xe2x80x94COO-ethyl or xe2x80x94CH2xe2x80x94COOxe2x80x94Na; especially preferably phenyl or benzyl, most especially phenyl;
(3) R in the compounds of formulae (II), (III), (IV) and (VI) is SR6 or xe2x80x94(CH2)nxe2x80x94SR6 and
R6 is C1-C8alkyl, aryl-C1-C4alkyl, arylthio-C1-C4alkyl, heterocycyl-C1-C4alkyl, heterocycyl-thio-C1-C4alkyl, C2-C4alkenyl, aryl-C2-C4alkenyl, heterocycyl-C2-C4alkenyl, C2-C4alkynyl, aryl-C2-C4alkynyl, heterocycyl-C2-C4alkynyl, cyclohexyl, aryl or heterocycyl;
especially C1-C4alkyl, 
xe2x80x83n is 1 or 2, preferably 2; and X and X1 are as defined in the compounds (II) and (III);
(4) X in the compounds of formulae (III) and (IV) is chlorine or bromine.
The reactions of process steps a) to f) described hereinbefore and hereinafter are carried out in a manner known per se, for example in the absence or, customarily, in the presence of a suitable solvent or diluent or of a mixture thereof, the reactions being carried out, as required, with cooling, at room temperature or with heating, for example in a temperature range of approximately from xe2x88x9280xc2x0 C. to the boiling temperature of the reaction medium, preferably from approximately xe2x88x9220xc2x0 C. to approximately +120xc2x0 C., especially from 20xc2x0 C. to 80xc2x0 C., and, if necessary, in a closed vessel, under pressure, under an inert gas atmosphere and/or under anhydrous conditions. Especially advantageous reaction conditions can be taken from the Examples.
The reactants can in each case be reacted with one another as such, i.e. without the addition of a solvent or diluent, for example in the molten state. However, the addition of an inert solvent or diluent or of a mixture thereof is in most cases advantageous. There may be mentioned as examples of such solvents and diluents:
aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, such as benzene, toluene, xylene, mesitylene, Tetralin, chlorobenzene, dichlorobenzene, bromobenzene, nitrobenzene, nitromethane, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, tetrachloromethane, dichloroethane, trichloroethene or tetrachloroethene; esters, such as ethyl acetate, methyl acetate, dimethyl carbonate, diethyl carbonate, ethoxyethyl acetate, methoxyethyl acetate, ethyl formate; ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, dimethoxydiethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone, methyl ethyl ketone or methyl isobutyl ketone; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol or glycerol; amides, such as N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide; nitriles, such as acetonitrile or propionitrile; and sulfoxides, such as dimethyl sulfoxide; or mixtures of such solvents. If the reaction in question is carried out in the presence of a base, bases such as triethylamine, pyridine, N-methylmorpholine or N,N-diethylaniline in excess may also serve as solvent or diluent. Suitable solvents for the reaction in question can be taken from the Examples.
Process Step a)
The reaction is preferably carried out in a temperature range of from xe2x88x9240 to 160xc2x0 C., especially from xe2x88x9220 to 100xc2x0 C., customarily from xe2x88x9220 to 25xc2x0 C.
Solvents that are inert under the prevailing reaction conditions are used, such as aliphatic and aromatic hydrocarbons, halogenated hydrocarbons, lower carboxylic acids, esters, nitriles, amides, ethers; for example: petroleum ether, pentane, hexane, heptane, chlorobenzene, methylene chloride, ethylene chloride, bromochloromethane, chloroform, carbon tetrachloride, tetrachloroethylene, acetic acid, ethyl acetate, acetonitrile, dimethylformamide, dimethylacetamide, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; or a mixture thereof; customarily: chlorobenzene, methylene chloride, bromochloromethane, ethyl acetate, acetonitrile, nitrobenzene, nitromethane; or mixtures of such solvents.
Water or a base may be added to the reaction mixture, if desired. Bases for facilitating the reaction are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides, alkanolates, acetates, carbonates, dialkylamides or alkylsilylamides; alkylamines, alkylenediamines, free or N-alkylated, saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxides and also carbocyclic amines. Examples are sodium hydroxide, sodium hydride, sodium amide, sodium methanolate, sodium acetate, sodium carbonate, potassium tert-butanolate, potassium hydroxide, potassium carbonate, potassium hydride, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, calcium hydride, triethylamine, diisopropylethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, quinuclidine, N-methylmorpholine, benzyltrimethylammonium hydroxide and also 1,5-diazabicyclo[5.4.0]-undec-5-ene (DBU). Preferred additives are sodium hydrogen carbonate and water. The procedure generally yields a free compound of formula (III) (m=0). However, the compounds of formula (III) can in many cases also be captured in the form of the hydrohalides, for example for the purpose of simpler isolation. The hydrohalides of formula (III), wherein m is 1, can then be converted into a free compound of formula (III) by the addition of a base or, alternatively, without a base at elevated temperature, preferably at from 40xc2x0 C. to 140xc2x0 C.
Suitable halogenating agents are especially chlorine, bromine, iodine, POCl3, PCl3, PCl5, SO2Cl2 or SO2Br2, preferably chlorine, bromine or SO2Cl2.
Process Step b)
The same conditions as under process a) apply in respect of solvents and temperatures; however, the reaction is carried out without the addition of a base.
The reaction is preferably carried out under normal pressure.
The reaction time is not critical; a reaction time of from 0.1 to 24 hours, especially from 0.5 to 6 hours, is preferred.
The product is isolated by the customary methods, for example by means of filtration, crystallisation, distillation or chromatography, or any suitable combination of such methods.
Process Step c)
The solvents and bases used can be taken from the details given with regard to process step a).
The reaction is preferably carried out at a temperature of from approximately 0xc2x0 C. to approximately +180xc2x0 C., especially at from approximately +10xc2x0 C. to approximately +80xc2x0 C., in many cases at from room temperature to the reflux temperature of the solvent. In an especially preferred form of variant c), a compound of formula (IV) is reacted at from 0xc2x0 C. to 120xc2x0 C., especially from 20xc2x0 C. to 80xc2x0 C., preferably from 30xc2x0 C. to 60xc2x0 C., in an ester, especially in dimethyl carbonate, and preferably in the presence of a base, especially K2CO3.
The reaction is preferably carried out under normal pressure.
The reaction time is not critical; a reaction time of from 0.1 to 48 hours, especially from 0.5 to 12 hours, is preferred.
The product is isolated by the customary methods, for example by means of filtration, crystallisation, distillation or chromatography, or any suitable combination of such methods.
Process Step d) and e)
Bases are customarily used to facilitate the reaction; they are of the same type as those mentioned under process step a).
The reactants can be reacted with one another as such, i.e. without a solvent or diluent, for example in the molten state. However, the addition of a solvent or diluent is in most cases advantageous. Examples of such solvents and diluents are: water; aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, for example benzene, toluene, xylene, mesitylene, Tetralin, chlorobenzene, dichlorobenzene, bromobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethene or tetrachloroethene; esters, such as ethyl acetate, methyl acetate, dimethyl carbonate, diethyl carbonate, methyl formate, ethyl formate, ethoxyethyl acetate, methoxyethyl acetate; ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, dimethoxydiethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone or methyl isobutyl ketone; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol or glycerol; amides, such as N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide; nitriles, such as acetonitrile or propionitrile; and sulfoxides, such as dimethyl sulfoxide; or mixtures of such solvents. If the reaction is carried out in the presence of a base, bases such as triethylamine, pyridine, N-methylmorpholine or N,N-diethylaniline in excess may serve as solvent or diluent.
The reaction may alternatively be carried out in a heterogeneous two-phase mixture, for example a mixture of organic solvents or an organic solvent and an aqueous phase, if necessary in the presence of a phase-transfer catalyst, for example a crown ether or a tetraalkylammonium salt.
In a preferred embodiment of variant d), the reaction is carried out at a temperature between 0xc2x0 C. to about +180xc2x0 C., especially between +10xc2x0 C. and +80xc2x0 C., in may cases between ambient temperature and the refluxing temperature of the solvent. In a especially preferred embodiment of variant d), the compound of the formula (III) is reacted with a compound of the formula (V) at between 0xc2x0 C. and 120xc2x0 C., especially between 20xc2x0 C. and 80xc2x0 C., preferably between 60xc2x0 C. and 80xc2x0 C., in an amide, preferably N,N-dimethyl-formamide, preferably in the presence of a base, especially K2CO3.
The reaction is preferably carried out under normal pressure.
The reaction time is not critical; a reaction time of from 0.1 to 48 hours, especially from 0.5 to 12 hours, more especially from 3 to 12 hours, is preferred.
The product is isolated by the customary methods, for example by means of filtration, crystallisation, distillation or chromatography, or any suitable combination of such methods.
The yields achieved are customarily good. A yield of 80% of the theoretical value can often be obtained.
Preferred conditions under which the reaction is carried out can be taken from the Examples.
For process step e) the same process conditions as under variant d) apply, however, an additional equivalent of a base of the type indicated under process step a) is added to the reaction mixture; preferably, at least three molar equivalents of base are added.
In a preferred embodiment of variant e), a compound of the formula (IV) is reacted with a compound of the formula (V), at a temperature between 0xc2x0 C. and 120xc2x0 C., especially between 20xc2x0 C. and 80xc2x0 C., preferably between 30xc2x0 C. and 60xc2x0 C., in a ketone, preferably methylethylketon, preferred in the presence of a base, especially K2CO3, preferably in the presence of a phase transfer catalyst, especially 1-(chloromethyl)4-aza-1-azoniabicyclo[2.2.2] octanechloride. In another preferred embodiment of variant e) a compound of the formula (IV) is reacted with a compound of the formula (V) at between 0xc2x0 C. and 120xc2x0 C., preferably 20xc2x0 C. and 80xc2x0 C., especially preferred between 30xc2x0 C. and 60xc2x0 C., in an ester, especially dimethylcarbonate, preferably in the presence of a base, especially K2CO3.
Process Step f)
Suitable halogenating agents are, for example, elementary chlorine, Javelle water, polysulfur dichloride, sulfur dichloride, phosphorus trichloride, phosphorus pentachloride, or mixtures of two or more of those reagents; especially elementary chlorine, Javelle water, sulfur dichloride or a mixture of those compounds, more especially Javelle water.
The reactants can be reacted with one another as such, i.e. without a solvent or diluent, for example in the molten state. However, the addition of a solvent or diluent is in most cases advantageous. Examples of such solvents and diluents are: water; acids such as, for example, hydrochloric acid, sulfuric acid, formic acid or acetic acid; aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, for example benzene, toluene, xylene, mesitylene, Tetralin, chlorobenzene, dichlorobenzene, bromobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethene or tetrachloroethene; esters, such as ethyl acetate; ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, dimethoxydiethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone, methyl ethyl ketone or methyl isobutyl ketone; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol or glycerol; amides, such as N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide; nitriles, such as acetonitrile or propionitrile; and sulfoxides, such as dimethyl sulfoxide; or mixtures of such solvents. In a preferred form, the reaction is carried out in a halogenated hydrocarbon, especially in dichloromethane. In an especially preferred form, the reaction is carried out in an aqueous acid, for example hydrochloric acid.
The reaction is preferably carried out at a temperature of from approximately 0xc2x0 C. to approximately +180xc2x0 C., especially at from approximately +10xc2x0 C. to approximately +80xc2x0 C., in many cases at from room temperature to the reflux temperature of the solvent. In a preferred form of variant f), the reaction is carried out at from 0xc2x0 C. to 120xc2x0 C., especially at from 10xc2x0 C. to 50xc2x0 C., preferably in aqueous hydrochloric acid.
The reaction is preferably carried out under normal pressure.
The reaction time is not critical; a reaction time of from 0.1 to 48 hours, especially from 2 to 12 hours, is preferred.
The product is isolated by the customary methods, for example by means of filtration, crystallisation, distillation or chromatography, or any suitable combination of such methods.
The yields achieved are customarily good. A yield of 50% of the theoretical value or above can often be obtained.
Preferred conditions under which the reaction is carried out can be taken from the Examples.
Salts of compounds of formulae (I) to (VI) can be prepared in a manner known per se. For example, acid addition salts are obtained by treatment with a suitable acid or a suitable ion exchange reagent, and salts with bases are obtained by treatment with a suitable base or a suitable ion exchange reagent.
Salts of compounds of formulae (I) to (VI) can be converted into the free compounds of formulae (I) to (VI) in customary manner; acid addition salts, for example, by treatment with a suitable basic agent or a suitable ion exchange reagent, and salts with bases, for example, by treatment with a suitable acid or a suitable ion exchange reagent.
Salts of compounds of formulae (I) to (VI) can be converted into different salts of compounds of formulae (I) to (VI) in a manner known per se; acid addition salts, for example, can be converted into different acid addition salts, for example by treating a salt of an inorganic acid, such as a hydrochloride, with a suitable metal salt, such as a sodium, barium or silver salt, of an acid, for example silver acetate, in a suitable solvent in which an inorganic salt that forms, for example silver chloride, is insoluble and therefore separates out of the reaction mixture.
Depending on the procedure and the reaction conditions, the compounds of formulae (I) to (VI) having salt-forming properties can be obtained in free form or in the form of salts.
The compounds of formulae (I) to (VI) and in each case, where applicable, their tautomers, in each case in free form or in salt form, may be in the form of one of the possible isomers or in the form of a mixture thereof, for example, depending on the number of asymmetric carbon atoms occurring in the molecule and their absolute and relative configuration, and/or depending on the configuration of non-aromatic double bonds occurring in the molecule, in the form of pure isomers, such as antipodes and/or diastereoisomers, or in the form of mixtures of isomers, such as mixtures of enantiomers, for example racemates, mixtures of diastereoisomers or mixtures of racemates; the invention relates both to the pure isomers and to all possible mixtures of isomers and is to be interpreted as such hereinbefore and hereinafter, even if stereochemical details are not mentioned specifically in every case.
Mixtures of diastereoisomers and mixtures of racemates of compounds of formulae (I) to (VI) which may be obtained by the process according to the starting materials and procedures chosen, or which are obtainable by another method, or their salts, can be separated into the pure diastereoisomers or racemates in known manner on the basis of the physicochemical differences between the constituents, for example by means of fractional crystallisation, distillation and/or chromatography.
Mixtures of enantiomers, such as racemates, that are obtainable in a corresponding manner can be resolved into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, by chromatography on chiral adsorbents, for example high pressure liquid chromatography (HPLC) on acetylcellulose, with the aid of suitable microorganisms, by cleavage with specific, immobilised enzymes, via the formation of inclusion compounds, for example using chiral crown ethers, only one enantiomer being complexed, or by conversion into diastereoisomeric salts, for example by reacting a basic end-product racemate with an optically active acid, such as a carboxylic acid, for example camphoric, tartaric or malic acid, or a sulfonic acid, for example camphorsulfonic acid, and separating the mixture of diastereoisomers so obtained, for example on the basis of their different solubilities by fractional crystallisation, into the diastereoisomers, from which the desired enantiomer can be freed by the action of suitable, for example basic, agents.
Apart from by separation of corresponding mixtures of isomers, pure diastereoisomers and enantiomers can be obtained according to the invention also by generally known methods of diastereoselective and enantioselective synthesis, for example by carrying out the process according to the invention using starting materials having correspondingly suitable stereochemistry.
The compounds of formulae (I) to (VI) and their salts can also be obtained in the form of their hydrates and/or include other solvents, for example solvents that may have been used for the crystallisation of compounds that occur in solid form.
The invention relates to all those forms of the process according to which a compound obtainable as starting material or intermediate at any stage of the process is used as starting material and all or some of the remaining steps are carried out, or a starting material is used in the form of a derivative or salt and/or in the form of its racemates or antipodes or, especially, is formed under the reaction conditions.
Compounds of formulae (I), (III), (IV), (V) and (VI) obtainable in accordance with the process or by another method can be converted into different corresponding compounds in a manner known per se.
In the process of the present invention there are preferably used those starting materials and intermediates, in each case in free form or in salt form, which lead to the compounds of formulae (I) to (VI) described at the beginning as being especially valuable, or their salts.
The invention relates especially to the preparation processes described in Examples P1 to P4.
The present invention relates also to the compounds of formula (IV) and, where applicable, their E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in each case in free form or in salt form, wherein R is as defined above for formula (I).
The present invention relates also to processes
a) for the preparation of a compound of formula (III) from a compound of formula (II);
b) for the preparation of a compound of formula (IV) from a compound of formula (II);
c) for the preparation of a compound of formula (III) from a compound of formula (IV); and
e) for the preparation of a compound of formula (VI) from a compound of formula (IV) and a compound of formula (V), and
f) for the preparation of a compound of formula (VI) from a compound of formula (III) and a compound of formula (V).
For substituents R in the compounds of formulae (II), (III), (IV) and (VI), the same preferred meanings as mentioned above in the processes for the preparation of the compounds of formula (I) apply.
The compounds of formulae (I), (II), (III), (V) and (VI) are known, for example as intermediates in the preparation of pesticides, or they can be prepared in accordance with processes known per se.